1. Field of the Invention (Technical Field)
The present invention relates to formulations and methods for treatment of sexual dysfunction, including female sexual dysfunction, by administration of selected doses of a melanocortin agonist. In particular, the present invention relates to methods for the treatment of female sexual dysfunction while reducing or minimizing side-effects, or adverse effects, associated with the administration of melanocortin agonists. More specifically, the invention relates to the pharmaceutical compositions in which the melanocortin agonist is bremelanotide and methods in which these pharmaceutical compositions are administered to patients for the treatment of female sexual dysfunction, including specifically female sexual dysfunction in premenopausal women, while reducing or minimizing side effects.
2. Description of Related Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
It is known that agonists of the melanocortin receptor, and particular melanocortin 4 receptor (MC4-R) agonists, may be employed for treatment of sexual dysfunction. See, for example, L. H. T. Van der Ploeg, W. J. Martin, A. D. Howard, R. P. Nargund et al., A role for the melanocortin 4 receptor in sexual function. Proc. Natl. Acad. Sci. USA 99:11381-86 (2002). The cyclic, heptapeptide melanocortin receptor agonist Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH, with the USAN adopted name bremelanotide and formerly known as PT-141, as further disclosed in U.S. Pat. Nos. 6,579,968 and 6,794,489, has been employed in clinical trials for sexual dysfunction, including both male erectile dysfunction (ED) and female sexual dysfunction or disorder (FSD).
There has been substantial progress in the definition and classification of the range of disorders that comprise FSD. The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) recognizes four major disorders that define FSD: decreased sexual desire, decreased sexual arousal, dyspareunia, and difficulty in achieving orgasm. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text revision ed. Washington, D.C.: American Psychiatric Publishing, Inc., 2000. In the United States approximately 43% of adult women experience some form of female sexual arousal disorder (FSAD) and/or hypoactive sexual desire disorder (HSDD), with approximately 22% of these women reporting being distressed by their sexual dysfunction. E. O. Laumann, A. Paik and R. C. Rosen, Sexual dysfunction in the United States: prevalence and predictors. JAMA 281:537-544 (1999); and, J. L. Shifren, B. U. Monz, P. A. Russo, A. Segreti and C. B. Johannes, Sexual problems and distress in United States women: prevalence and correlates. Obstet Gynecol 112:970-978 (2008). The current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), released in May 2013 by the American Psychiatric Association, revised the classification of female sexual dysfunction, replacing FSAD and HSDD with a new diagnosis of female sexual interest and arousal disorder (FSI/AD), and expanding the current concept of FSD to include receptivity to and initiation of sexual activity as part of the diagnostic heuristic. However, definitions of FSAD and HSDD remain in use, and are consistent with the description of female sexual dysfunction in the current version of the International Classification of Diseases (ICD-10).
Sexual therapy and education presently form the basis of treatment for FSAD and/or HSDD. Pharmaceutical treatments are limited; no drug is currently approved in the United States and one drug was approved in the European Union but subsequently withdrawn (INTRINSA®, a testosterone transdermal patch previously marketed by Warner Chilcott).
The female sexual response cycle is complex and dependent on physiological, psychological, and social factors. For many women, spontaneous desire is not the motivating factor to engage in sexual activity. Frequently, desire is a consequence of subjective arousal caused by a variety of sexual stimuli. An understanding of the female sexual response cycle provides a basis for the design and development of pharmacological interventions for treating FSAD and/or HSDD.
The mechanisms and corresponding pharmaceutical therapies underlying female sexual response are different from those underlying male sexual response. For instance, male sexual response involves both central nervous system function as well as nitric oxide production leading to an increase in blood flow to the penis. Conversely, female sexual response is dominated by central nervous system function, while the nitric oxide production pathway is of minor importance compared to results in men. Therefore, while therapies for treatment of male sexual dysfunction can be targeted to either or both mechanisms of action, therapies for treatment of female sexual dysfunction typically must be targeted to and must rely on the central nervous system function. A. M. Shadiack, S. D. Sharma, D. C. Earle, C. Spana and T. J. Hallam, Melanocortins in the Treatment of Male and Female Sexual Dysfunction. Current Topics in Medicinal Chemistry 7:1137-1144 (2007). Thus phosphodiesterase 5 (PDE-5) inhibitors such as sildenafil, tadalafil or vardenafil are effective in men with erectile dysfunction through a mechanism involving selective inhibition of PDE-5, thereby preventing the hydrolysis of cyclic guanosine monophosphate, resulting in increased blood flow to the penis. However, in women with female sexual dysfunction while PDE-5 inhibitors have some effect on genital vasocongestion, the drugs have little or no effect on treatment of female sexual dysfunction, including treatment of sexual arousal problems. M. L. Chivers and R. C. Rosen, Phosphodiesterase type 5 inhibitors and female sexual response: faulty protocols or paradigms? J. Sex. Med. 7:858-72 (2010).
Both animal and human studies have suggested that bremelanotide has central nervous system effects unrelated to local genital vasocongestion. In animal studies utilizing female rats, a selective pharmacological effect on appetitive sexual behavior was observed, with subcutaneous injections of bremelanotide inducing the immediate-early gene product Fos in a variety of limbic and hypothalamic structures, and increasing dopamine release in the medial preoptic area. J. G. Pfaus, A. Shadiack, T. Van Soest, M. Tse and P. Molinoff, Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist. Proc. Natl. Acad. Sci. USA 101:10201-4 (2004); J. Pfaus, F. Giuliano and H. Gelez, Bremelanotide: an overview of preclinical CNS effects on female sexual dysfunction. J. Sex. Med. 4:269-279 (2007). In humans, statistically relevant reported feelings of sexual arousal in women diagnosed with sexual arousal disorder were observed following a single intranasal dose of 20 mg of bremelanotide, but without statistically relevant differences, compared to placebo, in vaginal pulse amplitude measures. L. E. Diamond, D. C. Earle, J. R. Heiman, R. C. Rosen, M. A. Perelman and R. Harning, An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist. J. Sex. Med. 3:628-638 (2006). This is in contrast to the effect in men diagnosed with erectile dysfunction, where statistically significant erectile response compared to placebo, as determined by a plethysographic device measuring penile responses, with concomitant increased blood flow in the genital region, were seen with subcutaneous injection of either a 4 or 6 mg dose of bremelanotide. Shadiack, 2007, supra.
It has been reported in the literature that MC4-R agonists induce an adrenergic response, resulting in an increase in blood pressure and heart rate. See, for example, J. J. Kuo, A. A. Silva and J. E. Hall, Hypothalamic melanocortin receptors and chronic regulation of arterial pressure and renal function. Hypertension 41:768-774 (2003); J. J. Kuo, A. A. da Silva, L. S. Tallam and J. E. Hall, Role of adrenergic activity in pressor responses to chronic melanocortin receptor activation. Hypertension 43:370-375 (2004); U. Nordheim, J. R. Nicholson, K. Dokladny, P. Dunant and K. G. Hofbauer, Cardiovascular responses to melanocortin 4-receptor stimulation in conscious unrestrained normotensive rats. Peptides 27:438-443 (2006).
Adverse events have been observed with melanocortin agonists, including bremelanotide, primarily relating to an increase in blood pressure, and nausea and vomiting, both immediate and delayed.
There is a need for a therapeutic method for treatment of sexual dysfunction, including but not limited to FSD, by means of administration of a melanocortin agonist which provides the desired therapeutic benefit, but which does not induce, or does not significantly induce, or which reduces or minimizes adverse cardiovascular and other effects, such adverse effects including but not limited to increases in systolic blood pressure, diastolic blood pressure, heart rate or incidence of nausea or vomiting. It is against this background that the invention was made.